Institute of Biophysics, Academy of Sciences of the Czech Republic, vvi, Kralovopolska 135, 612 65 Brno, Czech Republic.
Mol Pharm. 2010 Dec 6;7(6):2093-102. doi: 10.1021/mp100080e. Epub 2010 Oct 25.
Before the active form of a Pt drug reaches its major pharmacological target in the cell nucleus, the Pt complex has to accumulate in cells, and during its transportation into cells and inside cells, it reacts with various biomolecules. Satraplatin is the first orally administered Pt drug under active clinical investigation. The major metabolite of this Pt(IV) complex is its Pt(II) analogue (JM118), which also has significant anticancer properties. Here we report the role of active transport in cellular entry of satraplatin and JM118 and interactions of these Pt complexes with glutathione. The results reveal that the organic cation transporters may play a more important role in the mechanism of cytotoxicity of JM118 than in the cytotoxicity of cisplatin. In contrast, satraplatin is a poor substrate of these transporters. In addition, satraplatin reacts with glutathione with the rate markedly lower than JM118 and cisplatin. Interestingly, satraplatin can be activated by glutathione allowing it to react with DNA, although to a much lower extent than in the case of another Pt(IV) drug tetraplatin.
在铂类药物的活性形式到达细胞核中的主要药理靶点之前，铂配合物必须在细胞中积累，并且在其进入细胞和细胞内的运输过程中，它会与各种生物分子发生反应。Satraplatin 是正在积极临床研究的第一个口服铂类药物。该铂（IV）配合物的主要代谢物是其 Pt(II)类似物（JM118），它也具有显著的抗癌特性。在这里，我们报告了主动转运在 Satraplatin 和 JM118 的细胞内摄取以及这些铂配合物与谷胱甘肽相互作用中的作用。结果表明，有机阳离子转运体在 JM118 的细胞毒性机制中可能比顺铂的细胞毒性机制中发挥更重要的作用。相比之下，Satraplatin 是这些转运体的不良底物。此外，Satraplatin 与谷胱甘肽的反应速率明显低于 JM118 和顺铂。有趣的是，Satraplatin 可以被谷胱甘肽激活，从而允许其与 DNA 反应，尽管其程度远低于另一种铂（IV）药物四铂。
